Physics of compartmentalization: How phase separation and signaling shape membrane and organelle identity

Abstract

Compartmentalization of cellular functions is at the core of the physiology of eukaryotic cells. Recent evidences indicate that a universal organizing process - phase separation - supports the partitioning of biomolecules in distinct phases from a single homogeneous mixture, a landmark event in both the biogenesis and the maintenance of membrane and non-membrane-bound organelles. In the cell, 'passive' (non energy-consuming) mechanisms are flanked by 'active' mechanisms of separation into phases of distinct density and stoichiometry, that allow for increased partitioning flexibility and programmability. A convergence of physical and biological approaches is leading to new insights into the inner functioning of this driver of intracellular order, holding promises for future advances in both biological research and biotechnological applications.

Fig. 1

Symmetry breaking and generation of cellular functions. In asymmetric cell division, fate determinants are distributed asymmetrically between the mother and daughter cell . In chemotactic cells, different molecular factors accumulate in the growing anterior part and in the retracting posterior part of the cell . During epithelial tissue morphogenesis, the apical, lateral and basal regions of the cell acquire different molecular identities , .

Fig. 2

Mixing-demixing transition. Left: schematic representation of the formation of phase-separated domains in a ‘sea’ of the mixed phase. Center: phase diagram of the process. Right: potential part of the free energy in the phase-coexistence region, with the characteristic bistable shape; the two potential wells correspond to the two stable phases.

Fig. 3

Active phase separation in the cytosol . Soluble A-molecules are converted to phase-separating B-molecules in the proximity of a catalytic core (dark red). An autocatalytic component reinforces the conversion of A into B. Additionally, the interconversion of the A- and B-molecules can also take place by first-order reactions.

Fig. 4

Left: abstract model for active phase separation on lipid membranes , , , . Right: phase diagram. Concentrations are measured in units of ${\text{A}}^{\mathrm{tot}}+{\text{B}}^{\mathrm{tot}}$; the graph is symmetric with respect to the vertical axis centered in $k_{\text{A}}^{\text{c}}{\text{E}}_{\text{A}}^{\mathrm{tot}}/k_{\text{B}}^{\text{c}}{\text{E}}_{\text{B}}^{\mathrm{tot}}$ (here assumed to be unity).

Fig. 5

Nucleation and coarsening of selforganized domains in biological phase separation (reproduced from the original with permission, in modified form); a) prion-like FUS protein, associated with the neurodegenerative disease ALS ; b) LAT protein, taking part in T cell receptor signal transduction ; c) stress granules ; d) post-synaptic densities ; e) nucleoli and extranucleolar droplets ; f) polarity establishment in yeast ; g) simulation of the coarsening kinetics of nucleoli and extranucleolar droplets ; h) simulation of coarsening kinetics in the establishment of cell polarity , .